Acute excessive consumption of alcoholic beverages leads, after a delay, to a post-intoxication period known as the hangover, which consists of throbbing headache as well as numerous other unpleasant physical symptoms. Hangover has many socioeconomic consequences, including reduced productivity and increased accident risk. Hangover headache proneness has been associated with increased risk for future development of alcohol use disorders. How hangover headache plays a role in the etiology of alcohol use disorders as well as other alcohol-related problems remains an open question, largely because the factors and neuronal mechanisms that mediate the hangover symptoms, including the headache are poorly understood. This lack of knowledge can be attributed, in part to the paucity of clinical studies and the almost complete lack of basic research on the physiological and neurophysiological processes underlying the phenomenon. We have previously established a unique animal model for studying the activity and mechanosensitivity of meningeal nociceptors, the peripheral neuronal population that has been most directly implicated in the genesis of headache. We now propose to use this animal model to investigate for the first time the factors that play a role in mediating the hangover headache, one of the most common symptoms of the hangover state. Using in vivo single unit recordings of meningeal nociceptors in anesthetized rats, we propose to start this line of investigation by addressing the identity of the alcohol-related substances as well as the neural processes that might potentially contribute to the hangover headache. Specific aim 1 will examine time-course and dose- related effects of acute ethanol administration on the activity and mechanosensitivity of meningeal nociceptors. Specific Aim 2 will determine the relative contribution of ethanol's first metabolite acetaldehyde in mediating meningeal nociceptor activation and sensitization following administration of intoxicating doses of ethanol. Specific Aim 3 will examine whether methanol, one of the major toxic congeners found in alcoholic beverages or its metabolites formate and formic acid increase the activity and mechanosensitivity of meningeal nociceptors and further determine whether methanol can enhance or prolong the activation and sensitization of meningeal nociceptors associated with acute ethanol intoxication. These experiments are the first methodological step in the study of the neurobiological mechanisms underlying a major hangover symptom, the headache. Data from this exploratory project will begin to fill the gaps in our knowledge regarding the factors and processes the may contribute to the hangover headache and provide much needed data to generate further testable hypotheses on the origin of the headache and potentially other hangover symptoms. Data will be instrumental in future studies that address the question of how the degree of sensitivity to hangover is related to differences in the propensity of developing alcoholism and potentially other hangover- related health problems. PUBLIC HEALTH RELEVANCE: Increased hangover frequency and susceptibility are associated with increased risk for future development of alcohol use disorders as well as other alcohol related health problems. How the degree of sensitivity to hangover is related to differences in the propensity of developing alcoholism is unknown, in part because of the poor understanding of the mechanisms underlying the hangover state. This project will begin to explore, using an animal model, the mechanisms underlying the hangover headache, one of the most common and disabling symptoms of the hangover.